The drug compound having the adopted name Nilotinib has chemical name 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, and is structurally represented by formula (I):

Nilotinib is a small-molecule tyrosine kinase inhibitor approved for the treatment of imatinib-resistant chronic myelogenous leukemia. Structurally related to Imatinib, it was developed based on the structure of the Abl-imatinib complex to address Imatinib intolerance and resistance.
Nilotinib is a selective Bcr-Abl kinase inhibitor that is 10-30 fold more potent than Imatinib. It has been available in the market in Europe since September 2009 as mono-hydrochloride mono-hydrate salt, form B under the tradename Tasigna®.
U.S. patent application Ser. No. 10/520,359 discloses Nilotinib and process for its preparation. The disclosed process involves the reaction of ethyl-3-amino-4-methylbenzoate (1) with cyanamide in presence of hydrochloric acid in ethanol followed by treatment with aqueous ammonium nitrate to provide 3-[(aminoiminomethyl)amino]-4-methyl-benzoic acid ethylester mononitrate (2); this intermediate, on further treatment with 3-(dimethylamino)-1-(pyridine-3-yl)prop-2-en-1-one (3) in presence of sodium hydroxide in ethanol, provides 4-methyl-3-{[4-(3-pyridinyl)-2-pyrimidinyl]amino}benzoic acid ethylester (4); said ethyl ester compound (4) was hydrolyzed using sodium hydroxide in ethanol solvent; the obtained 4-methyl-3-{[4-(3-pyridinyl)-2-pyrimidinyl]amino}benzoic acid (5) is coupled with 5-trifluoromethyl-3-[4-methyl-1H-imidazolyl]aniline (6) in the presence of diethylcyanophosphate and a base (triethylamine) in dimethylformamide to provide Nilotinib. The said process is represented in the following scheme:

A particularly useful salt of Nilotinib is Nilotinib hydrochloride monohydrate as disclosed in U.S. patent application Ser. No. 11/995,898. This application discloses two polymorphic forms of Nilotinib hydrochloride monohydrate, namely “Form A” and “Form B”. Said application also discloses various other salts of Nilotinib, namely monophosphate, diphosphate, sulfate, mesylate, esylate, besylate and tosylate and processes for their preparation. Example 1 of U.S. patent application Ser. No. 11/995,898 describes a process for preparing Nilotinib hydrochloride monohydrate, whose the resulting product is characterized by an X-Ray diffraction (XPRD) pattern having peaks at 7.4, 9.4, 11.6, 12.1. 15.8, 19.3, 22.1, 24.1 and 25.7±0.2 degrees 2-theta. Form B is described in U.S. patent application Ser. No. 11/995,898 as being hygroscopic and very poorly soluble in water.
International application publication No. WO 2007/015870 A2 describes substantially pure crystalline forms of Nilotinib hydrochloride designated as Form A, Form A′, Form A″, Form B, Form B′, Form Ss, Form Ss′, Form C, Form C′, Form Se, Form D, Form SE, mixture of Form B and Form D, and amorphous form of Nilotinib hydrochloride. Further, it also discloses substantially pure crystalline forms A and B of Nilotinib free base and substantially pure crystalline forms A and B of Nilotinib sulfate salt.
International application publication No. WO 2010/009402 discloses a process which involves the reaction of 4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acid with 5-trifluoromethyl-3-[4-methyl-1H-imidazolyl]aniline in the presence of thionyl chloride in N-methylpyrrolidine solvent to provide Nilotinib.
International application publication No. WO 2010/054056 A2 describes polymorphic forms of Nilotinib hydrochloride designated as forms T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, T13, T14, T15 T16, T17, T18, and T19. Further, it also describes solid dispersion of Nilotinib hydrochloride in combination with a pharmaceutically suitable excipient.
International application publication No. WO 2011/163222 describes polymorphic forms of Nilotinib hydrochloride designated as forms T20, T27, T28 and T29.
International application publication No. WO 2011/086541 A1 describes a crystalline form of Nilotinib hydrochloride monohydrate having an X-ray diffraction pattern comprising peaks at 5.70, 7.56, 9.82, 15.01, 17.31 and 27.68±0.2 degrees 2-theta and process for its preparation.
International application publication No. WO 2012/070062 A2 describes Nilotinib hydrochloride crystalline form H1, characterized by peaks in the powder x-ray diffraction spectrum having 2-theta angle positions at about 8.6, 11.4, 13.2, 14.3, 15.5, 17.3, 19.2 and 25.3±0.2 degrees and a process for its preparation.
US application publication No. 2013/0210847 A1 describes Nilotinib hydrochloride dihydrate, characterized by peaks in the powder X-ray diffraction pattern at 4.3, 8.7, 9.5, 11.3, 13.2, 14.4, 17.3, 18.6, 19.3, 20.8, 22.2 and 25.3 degrees 2-theta (±0.1 degrees 2-theta).
International application publication No. WO 2011/033307 discloses Nilotinib dihydrochloride and its hydrates, in particular Nilotinib dihydrochloride dihydrate characterized by XPRD, Differential Scanning calorimetry (DSC) and Thermogravimetric analysis (TGA). Also disclosed is a process for the preparation thereof and pharmaceutical compositions containing these compounds as well as the use of the compounds in the treatment of cancer.
Nilotinib dihydrochloride dihydrate disclosed in WO 2011/033307 is characterized by (i) an XPRD pattern comprising peaks at 7.18, 14.32, 23.34 and 27.62±0.2 degrees; and (ii) a DSC thermogram with endothermic peaks at about 107±2° C. and 251±2° C.
International application publication No. WO 2015/087343 discloses, in the Example 4, a process for the preparation of Nilotinib. The disclosed process involves a coupling reaction of 4-methyl-3-{[4-(3-pyridinyl)-2-pyrimidinyl]amino}benzoic acid (5) with 5-trifluoromethyl-3-[4-methyl-1H-imidazolyl]aniline (6) in presence of carbonyl diimidazole and imidazole hydrochloride in N-methylpyrrolidine as a solvent. After completion of the coupling reaction, the reaction mass was cooled and a sodium hydroxide solution was added. The disclosed process provides Nilotinib free base in 52.63% molar yield and has a purity of 99.84% by HPLC, containing 0.03% of 4-methyl-3-{[4-(3-pyridinyl)-2-pyrimidinyl]amino}benzoic acid (also name as acid impurity).
International application publication No. WO 2016/1513304 discloses, in example 1, a process for the preparation of Nilotinib dihydrochloride dihydrate. The disclosed process involves a coupling reaction of 4-methyl-3-{[4-(3-pyridinyl)-2-pyrimidinyl]amino}benzoic acid (5) with 5-trifluoromethyl-3-[4-methyl-1H-imidazolyl]aniline (6) in presence of thionyl chloride in N-methylpyrrolidone as a solvent. After completion of the coupling reaction, the reaction mass was cooled and water and acetone was added. The disclosed process provides Nilotinib free base. The Nilotinib free base was dissolved in a mixture of conc. HCl and methanol, being then filtered through hyflo. The obtained solution was concentrated to residue and the residue was dissolved in a mixture of water an methanol. The obtained solution was slowly added to the acetonitrile and thus obtaining a suspension of the product which was filtered to obtain the solid of title compound. The disclosed process provides thus Nilotinib dihydrochloride dihydrate in 67.27% molar yield, which is quite a low value of yield.